# Smoothened (hedgehog pathway)

Source: https://onco.cc/targets/smoothened/  
OnCo record `smoothened` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.

## Summary

Hedgehog ligand binding to PTCH1 releases SMO, a GPCR-like protein, to activate GLI transcription factors. PTCH1 loss (~70%) or SMO mutation (~10-20%) drives essentially all basal cell carcinoma, SHH-subgroup medulloblastoma (~30%) and Gorlin syndrome. Vismodegib (2012) and sonidegib (2015) treat advanced BCC; glasdegib (2018) with low-dose cytarabine treats unfit AML. Class toxicities (muscle spasms, dysgeusia, alopecia, teratogenicity) limit duration; SMO mutations (D473H, W535L) cause resistance; downstream GLI or SUFU-loss tumours do not respond.

## Fields

- Kind: Target
- Last checked: 2026-09-08
- Tags: gap-fill
- Symbol: SMO
- Class: other
- Biology: Seven-transmembrane Frizzled-class receptor; cholesterol binding to its cysteine-rich domain and transmembrane site activates it once PTCH1 inhibition is relieved, translocating to the primary cilium and derepressing GLI2/3.
- Where found: Basal cell carcinoma (PTCH1 ~70%, SMO ~10-20%); SHH medulloblastoma (~30% of medulloblastoma); Gorlin syndrome (germline PTCH1/SUFU); AML (pathway activity in leukaemic stem cells)

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Smoothened
- BCC genomics (Nat Genet 2016): https://doi.org/10.1038/ng.3525

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Basal cell carcinoma](https://onco.cc/cancers/basal-cell-carcinoma/), [Locally advanced and metastatic basal cell carcinoma](https://onco.cc/cancers/locally-advanced-bcc/), [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [SHH-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-shh/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- drugs: [Glasdegib](https://onco.cc/drugs/glasdegib/), [Patidegib](https://onco.cc/drugs/patidegib/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Vismodegib](https://onco.cc/drugs/vismodegib/)
- pathways: [Basal cell carcinoma (KEGG map)](https://onco.cc/pathways/basal-cell-carcinoma-signalling/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Invasion: proteases, adhesion & the invasive front](https://onco.cc/pathways/invasion-ecm-degradation/), [Proteoglycans in cancer](https://onco.cc/pathways/proteoglycans-in-cancer/)
- key papers: [Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma](https://onco.cc/key-papers/paper-bonilla-nat-genet/)
- terms: [Why people stop taking hedgehog inhibitors](https://onco.cc/terms/hedgehog-inhibitor-tolerability/)
- trials: [BOLT](https://onco.cc/trials/bolt/), [ERIVANCE BCC](https://onco.cc/trials/erivance/), [Patidegib gel in Gorlin syndrome (phase 2A)](https://onco.cc/trials/patidegib-gel-gorlin-phase-2/), [STEVIE (vismodegib in ordinary practice)](https://onco.cc/trials/stevie/), [VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma)](https://onco.cc/trials/vismoneo/)
- targets: [PTCH1 (Patched 1)](https://onco.cc/targets/ptch1/)

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